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The observation that curcumin can reach the brain following oral administration is consistent with the hypothesis that dietary curcumin may indeed benefit Alzheimer disease (AD) by dissociating amyloid plagues in the brain, at least based on the outcome in a transgenic mouse model of AD. The structure/function comparison between curcumin and tetrahydrocurcumin in this manuscript definitely supports that hypothesis.

Interestingly, Begum and collaborators report that anti-inflammatory bioactivities are primarily linked to the phenolic ring methoxy groups, while disaggregation of amyloid plaques in the brain is linked to the C = C double bonds of curcumin's dienone. The requirement for the C = C dienone structure might be unique for this role of biphenolic compounds. Indeed, this double bond structure is not necessary for anti-Aβ-aggregation bioactivity in other polyphenolic compounds. This is consistent with the recent observations (Wang et al., in press) that grape seed proanthocyanidin extracts (which do not contain the curcumin-type C = C dienone structure) exert anti-Aβ-oligomerization activity, and that oral administration of grape seed extract significantly reduced amyloid plaque in the brain of Tg2576 mouse model of AD, which shows coincidental cognitive deterioration.

Interestingly, while tetrahydrocurcumin did not disaggregate existing amyloid plaques, this molecule significantly reduced total soluble Aβ in the brain. Given that total soluble Aβ encompasses both monomeric Aβ as well as soluble high-molecular weight (HMW) oligomeric Aβ species, and that there is currently a consensus that HMW Aβ species in the brain are major modulators of cognitive deterioration in AD, it would be extremely interesting to assess whether oral administration of tetrahydrocurcumin might attenuate cognitive deterioration in Tg2576 mice by reducing the accumulation of soluble HMW Aβ species. If this proved to be the case, it is possible that the cognitive benefit of oral curcumin administration might be due, in part, to conversion and accumulation of tetrahydrocurcumin in the brain.

A major future task will be to understand why oral administration of curcumin has not led to detectable levels of curcumin in the plasma of human subjects! The possibility that other dietary factors might either promote or impede intestinal absorption of curcumin is extremely tantalizing and definitely requires further study. In the meantime, it might be worthwhile assessing whether curcumin metabolites such as tetrahydrocurcumin might be found in the blood following dietary administration of curcumin.